For maintenance of homeostasis, it is critical to keep a constant supply of glucose to the cells to avoid the occurrence of dysglycemia and its related metabolic imbalances. If left ignored or untreated, metabolic dysglycemia would lead to numerous metabolic diseases, including obesity, heart disease, hypertension, diabetes, chronic fatigue, accelerated aging, degenerative disease, as well as many mental and emotional problems. For this reason, it is important to identify and, at the same time, treat this condition early before costly and disabling degenerative conditions arise that can ruin the quality of life as well as shorten it.
Dysglycemia and diabetes show up very slowly, silently and dangerously. As disclosed by the American Diabetes Association, more than a third of American adults suffering from diabetes—more than five million people—are not even aware that they have the disease. Many will learn of their condition only after they develop a severe debilitating disorder, such as heart disease, stroke, impaired vision, kidney disease, nerve damage or impotence. American Diabetes Association: Facts and Figures, 2000, at www.diabetes.org/info/facts/facts_natl.jsp.
Diabetes or diabetes mellitus is a disease that occurs when the body cannot make use of the glucose in the blood for energy because either the pancreas is not able to make enough insulin or the insulin that is available is not effective. The early signs of diabetes are glucose intolerance and insulin resistance. There are two main types of diabetes mellitus: insulin-dependent (type 1) and noninsulin-dependent (type 2 or adult onset diabetes).
A third type of diabetes is the gestational diabetes that develops only in pregnant women with no previous history of diabetes. Nearly 135,000 U.S. women develop gestational diabetes each year. Typically, gestational diabetes clears up on its own after women have delivered their babies. But studies show that about 40% of women with gestational diabetes go on to develop type 2 diabetes within 15 years (NIH Publication No. 02-3873, May 2002).
In insulin-dependent diabetes (IDDM; type I diabetes), the pancreas makes little or no insulin because the insulin-producing beta cells have been destroyed. This usually appears at any age but usually occurs between infancy and the late 30's, most typically in childhood or adolescence. Treatment consists of daily insulin injections or use of an insulin pump, a planned diet and regular exercise, and daily self-monitoring of blood glucose. If the level of insulin is too low for a long period of time, the body begins to break down its stores of fat for energy. This causes the body to release fatty acids which are then converted into ketone bodies or ketoacids that are toxic at high levels. The result is called ketoacidosis, a severe condition that may put a person into a coma if not treated right away.
In noninsulin-dependent diabetes (NIDDM; type II diabetes or adult onset diabetes (AOD)), the pancreas cannot produce enough insulin or the body tissues become resistant to insulin. Because insulin is not available or is improperly used, the blood sugar level rises above the safety level. The patient's blood sugar level often rises gradually, taking several years to reach unsafe levels and cause symptoms. Thus, in some people, where the diabetic condition has not yet developed, normal or excessive levels of insulin compensate for such resistance. Over time however, insulin production often drops and resistance worsens. About 90-95% of all diabetic people have AOD. It is more common in people over the age of 40.
AOD is caused by a complicated interplay of genes, environment, insulin abnormalities (reduced insulin secretion in the beta cells and insulin resistance in muscle cells), increased glucose production in the liver, increased fat breakdown, and possibly defective hormonal secretions in the intestine. The recent dramatic increase of this disease indicates that lifestyle factors, such as obesity and sedentary lifestyle, may be strong contributory factors in releasing the genetic elements that cause the disease.
Insulin-stimulated glucose uptake is widely variable among individuals (Stern, M. P. and Mitchell, B. D. Genetics of Insulin Resistance. In G. M. Reaven and A. Laws (eds). Insulin Resistance, The Metabolic Syndrome X, p. 3-18, Humana Press Inc., Totowa, N.J., 1999). The degree of insulin resistance observed in normal individuals can equal that seen in diabetic individuals. Hence, it is now widely known that insulin resistance precedes the development of adult onset diabetes. It is also equally essential to acknowledge that mild or even severe insulin resistance may be found in individuals who will never develop diabetes. Genetic factors contribute to this normal variation in insulin resistance. The common forms of insulin resistance include skeletal muscle insulin resistance, hepatic insulin resistance and adipose tissue insulin resistance. The entire contents of G. M. Reaven and A. Laws, (eds), Insulin Resistance, The Metabolic Syndrome X, p. 3-18, Humana Press Inc., Totowa, N.J., 1999, are incorporated herein by reference in their entirety.
The cellular response to insulin is mediated through a specific insulin receptor in the plasma membrane. When insulin activates the receptor, the•-subunit is autophosphorylated at the juxtamembrane domain, the kinase domain, and the C-terminal domain. Full receptor autophosphorylation subsequently activates the protein tyrosine kinase receptor activity, which together are necessary for the cellular response to insulin (Kahn, C. R. et al., J. Clin. Invest. 82:8622-8626, 1988).
Insulin resistance is an impaired response to normal levels of exogenous or endogenous insulin in cells, tissues, the liver or the entire body. It can be caused by several factors, namely: (1) obesity factors (such as elevated levels of free fatty acids and the association of insulin resistance with cytokines, e.g., resistin and leptin (Mooradian A. D., Growth Horm. IGF Res. 11:Suppl A:S79-83, 2001; Ravussin, E. and Smith, S. R., Ann. N.Y. Acad. Sci. 967:363-78, 2002)); (2) proteins like calpains (Baier, L. J. et al., J. Clin. Invest. 106:819-21, 2000); (3) abnormal regulation of amylin and calcitonin gene-related peptide (CGRP) that affect both the circulatory and nervous system (Leighton, B. and Cooper, G. J., Nature 335:632-5, 1988; Haynes, J. M. et al. Diabetologia 40:256-61, 1997); (4) elevated levels of interleukin 6 (IL-6) and C-reactive protein (CRP) that act as inflammatory and damage markers (Hak, A. E. et al., J. Clin. Endocrinol. Metab. 86:4398-405, 2001; Pickup, J. C. et al., Diabetologia 40:1286-92, 1997); and (5) increased level of growth hormone during puberty (Dunger, D. B. and Cheetham, T. D., Horm. Res. 46:2-6, 1996; Halldin, M. U. et al., Clin. Endocrinol. (Oxf) 48:785-94, 1998).
The main cause of death in people with AOD, regardless of sex or age, is heart disease. Other complications associated with diabetes include nerve damage (neuropathy) and vascular abnormalities in both small and large blood vessels. Heart attacks account for 60% and stroke for 25% of deaths in all diabetics. People with diabetes are at risk for heart-risk conditions that include hypertension, high triglyceride levels and lower high density lipoprotein, blood clotting problems, neuropathy, and silent ischemia. To avoid some of these complications, diabetic patients are treated with statins to improve their cholesterol and lipid levels, e.g., pravastatin (Pravachol), simvastatin (Zocor), fluvastatin (Lescol), atorvastatin (Lipitor), and rosuvastatin (Crestor). Niacin can also be administered to improve the cholesterol profile but it also increases blood sugar level.
Drug therapy is one common approach to treatment of adult onset diabetes. Oral agents such as sulfonylureas (e.g., glyburide, glipizide, glimepiride), meglitinides, biguanides, thiazolinediones, and alpha-glucosidase inhibitors, singly or combined, with or without insulin replacement therapy are used currently.
Some forms of insulin analogues may be useful for patients having adult onset diabetes. However, the possible adverse effects of insulin on weight gain and the heart are troublesome. In fact, lower mortality rates were obtained with drug treatment therapy (metformin (8%), sulfonylurea (16%) and thiazolinediones (14%) than insulin treatment (28%)).
Metabolic Syndrome X (MS-X) is a condition that promotes atherosclerosis and increases the risk of cardiovascular events through the collection of independent and related complications or disorders. This condition itself has been variously referred to as “syndrome X,” “insulin resistance syndrome” (Li, C. et al., Diabetes Care 24: 2035-2042, 2001), “Reaven's syndrome” (Home, P., Diabet. Med. 6: 559-560, 1989), and “the metabolic cardiovascular risk syndrome” (Hjermann, I., J. Cardiovasc. Pharmacol. 20: S5-S10, 1992). The related complications or disorders of MS-X include dyslipidemia (hypertriglyceridemia and low high-density lipoprotein (HDL)-cholesterol), a prothrombotic state, type 2 diabetes (adult onset diabetes), insulin resistance/hyperinsulinemia, hypertension, and abdominal obesity. Grundy, S. M. Am J Cardiol. 81: 18B-25B, 1998.
Although the patient may not have any symptoms from MS-X, the attending physician could identify the following as signs of the condition: (1) elevated insulin levels, due to insulin resistance; (2) type II diabetes; (3) central obesity (a disproportionate amount of body fat in the abdominal region); (4) hyperlipidemia (high levels of fats (lipids) in the blood, which include LDL (“bad”) cholesterol and triglycerides. In addition, the size of the LDLs may be smaller than usual, which is more likely to promote atherosclerosis); (5) low level of HDL (“good”) cholesterol; (6) hypertension (high blood pressure); (7) elevated levels of blood factors that promote blood clotting, such as plasminogen activator inhibitor-1 (PAI-1) and fibrinogen; (8) hyperuricemia (high levels of uric acid in the blood); and (9) microalbuminuria (small amounts of the protein albumin, found on urine tests). Grundy S. M., Am. J. Cardiol. 83: 25F-29F, 1999.
Independently, each of these complications or disorders promotes atherosclerosis. However, when grouped together, they are increasingly atherogenic and enhance the risk of cardiovascular disease (CVD) at any low density lipoprotein cholesterol level. In addition to increasing a patient's risk of CVD, MS-X may enhance the development of stroke, type 2 diabetes (Lebovitz, H. E., Exp. Clin. Endocrinol. Diabetes 109: S135-S148, 2001), diabetic nephropathy, retinopathy, and distal neuropathy (Isomaa, B. et al., Diabetologia 44:1148-1154, 2001).
Using the above-mentioned features, one estimate suggests that as many as 50 to 75 million people in the United States may exhibit significant signs of MS-X by 2010. Hansen, B. C., Ann. NY Acad. Sci. 892: 1-24, 1999.
According to the World Health Organization (WHO) guideline, an individual is diagnosed to have MS-X if the features are present: a) hypertension (>140 mm Hg systolic or >90 mm Hg diastolic); (b) dyslipidemia, defined as elevated plasma triglycerides (150 mg/dL) and/or low high-density lipoprotein (HDL) cholesterol (<35 mg/dL in men, <39 mg/dL in women) concentrations; 3) obesity, defined as a high body mass index (BMI) (30 kg/m2) and/or a high waist-to-hip ratio (>0.90 in men, >0.85 in women); and 4) microalbuminuria (urinary albumin excretion rate•20•g/min). See WHO-International Society of Hypertension Guidelines for the Management of Hypertension. Guidelines Subcommittee. J. Hypertens. 17:151-183, 1999. By this standard, individuals with type 2 diabetes must meet only 2 of the criteria in order to be diagnosed with MS-X.
A similar guideline, established by the National Cholesterol Education Program (NCEP ATP III study) establishes that a person would have MS-X, if 3 or more of the following risk factors are present: (1) a waist circumference >102 cm (40 in) for men or >88 cm (37 in) for women; (2) a triglyceride level•150 mg/dL; (3) an HDL cholesterol level <40 mg/dL for men or <50 mg/dL for women; (4) blood pressure•130/•85 mm Hg; or (5) a fasting glucose•110 mg/dL. See JAMA 285: 2486-2497, 2001.
These guidelines assert that abdominal obesity rather than elevated BMI is more highly associated with MS-X and suggest that all patients with abdominal obesity should be evaluated for the possibility of this syndrome. In addition, ATP III guideline has a lower diagnostic threshold level than that of WHO for certain characteristics (i.e., HDL cholesterol and hypertension). Therefore, a higher proportion of the population meets the ATP III standard for the diagnosis of MS-X.
The central features of MS-X are all highly related, entail numerous physiological systems, and reveal a complex multifactorial etiology. In dyslipidemia, also known as the lipid triad, other lipid abnormalities, such as moderately raised (often high-normal) triglycerides, increased preponderance of small, dense LDL particles, and low levels of HDL cholesterol are included. Grundy, S. M. Circulation 95: 1-4, 1997. Dyslipidemia and insulin resistance are related metabolic conditions. Haffner, S. M. Am. J. Cardiol. 83: 17F-21F, 1999 and Ginsberg, H. N. and Huang, L. S., J. Cardiovasc. Risk 7: 325-331, 2000.
With respect to a prothrombotic state, insulin resistant patients often experience changes in coagulation factors that may promote arterial thrombosis and inflammation. Grundy, S. M. et al., Circulation 100: 1134-1146, 1999. A procoagulant state may increase the formation of atherosclerotic plaques and the size of thrombi following the rupture of plaques. Commonly identified conditions in the MS that are related to a prothrombotic state include activation of endothelial cells, promotion of LDL oxidation, enhanced platelet aggregation, activation of factor VII, increased levels of factor IX, factor X, and prothrombin, and increased concentrations of PAI-1. Peroxisome proliferator-activated receptor-α(PPAR-α), a major regulator of intra- and extracellular lipid metabolism, may play a role in atherogenic dyslipidemia and inflammation. Gervois, P. et al., Clin. Chem. Lab. Med. 38: 3-11, 2000. Activation of the PPAR-α ligand-binding domain may assist fatty acid metabolism in the liver by promoting transcription of certain target genes, such as fatty acid binding protein. In addition, PPARs may play a central role in regulating the interaction between HDL cholesterol and apolipoprotein (apo) B-containing lipoproteins. Pineda, T. I., et al., Curr. Opin. Lipidol. 10: 151-159, 1999.
Overproduction of insulin leads to hypertension. WHO guidelines suggest that patients receiving anti-hypertensive treatment and/or having elevated blood pressure (>140 mm Hg systolic or >90 mm Hg diastolic) are at risk for MS. J. Hypertens. 17: 151-183, 1999. Hypertension has been well established as a metabolic disorder and is predictive of insulin resistance. Lind, L. and Lithell, H. Am. Heart J. 125: 1494-1497, 1993. As many as 50% of the anti-hypertensive patients have comorbid insulin resistance and hyperinsulinemia. McLaughlin, T. and Reaven, G., Geriatrics 55: 28-35, 2000. The use of an appropriate pharmacologic agent to reduce blood pressure may lessen the signs of insulin resistance in patients who exhibit both conditions. Lowering elevated blood pressure may also improve a patient's lipid profile. Weidmann, P. et al., Am. Heart J. 125: 1498-1513, 1993.
Increased blood pressure independently increases the risk of atherosclerosis, presumably by promoting the entry of LDL into the subendothelial space, and may exacerbate other metabolic abnormalities. Hormstra, G. et al., Br. J. Nutr. 80:S113-S 146, 1998.
For diagnosis of MS-X, a variety of blood test are used to measure levels of glucose, insulin, triglycerides, cholesterol, uric acid, fibrinogen and PAI-1. In addition, blood pressure and body weight should be measured and evaluated.
Currently, the only known treatment strategies that addresses all the factor of MS-X are weight loss and exercise. Medications are given but physicians would usually encourage the MS-X patients to change their life style such as decreasing the amount of fats and oils in their diet, avoiding concentrated sweets, quitting smoking and avoiding excessive alcohol use.
Besides the above-mentioned strategies, several groups have disclosed the use of specific drugs to treat MS-X and its related complications. Below is a brief summary of their disclosures.
U.S. Pat. No. 6,166,049 discloses a method for the treatment or prophylaxis of syndrome X in a human or non-human mammal by administering an effective, non-toxic and pharmaceutically effective amount of an agonist of peroxisome proliferator-activator receptor-• and -• (PPAR-• and PPAR-•). The inclusion of PPAR-• in a PPAR-• anti-hyperglycaemic agent will result in a reagent with enhanced therapeutic potential in the syndrome X etiology due to an enhanced hypolipaedemic effect. The invention provides a prophetic example relating to the efficacy of the compounds on blood glucose and plasma lipids in a genetically diabetic mouse.
U.S. Pat. No. 6,197,765 discloses a treatment for MS-X and its related complications, including diabetes complications, by administering a dose of diazoxide to inhibit the release of insulin and proinsulin, lower weight, reduce levels of circulating cholesterol and triglycerides, lower blood pressure and prevent and reverse diabetic complications.
U.S. Pat. No. 6,410,339 discloses the use of synthetic cortisol agonists that have glucocorticoidal and/or mineral corticoidal effects, e.g., dexamethasone, for preparing a system to diagnose MS and its related conditions such as belly fatness, insulin resistance including risk of developing senile diabetes, i.e., diabetes type II, high blood fats and high blood pressure. The dose of cortisol agonist is in an interval where a difference is obtained in the inhibitory effect of the autoproduction of cortisol in individuals suffering from MS, compared to normal values.
U.S. application serial No. 20020165237 by Fryburg et al. teaches the use of selective cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 inhibitors, such as sildenafil, for the treatment of insulin resistance syndrome (IRS). Sildenafil has been shown to be effective in the treatment of male erectile dysfunction. Sildenafil increases the intracellular concentrations of nitric oxide (NO)-derived cGMP. This accumulation would amplify the vasodilatory, metabolic, and anti-atherogenic effects of the available nitric oxide and insulin. According to the inventors, such treatment may lead to clinically relevant improvements in blood pressure and/or blood sugar and/or lipids and/or uric acid, and/or procoagulant factors. This treatment can occur alone or in combination with other therapeutics that improve IRS which, in turn, should reduce the risk of the development of cardiovascular disease in some patients, as well as other complications of individual disorders (including, but not limited to diabetic neuropathy, nephropathy, and retinopathy).
U.S. application serial No. 20020037861 A1, by Plata-Salaman et al., discloses the use of anticonvulsant derivatives in preventing the development of type II diabetes mellitus and syndrome X. One of the anti-convulsant derivatives, 2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate (known as topiramate), has been demonstrated in clinical trials of human epilepsy to be effective as adjunctive therapy or as monotherapy in treating simple and complex partial seizures and secondarily generalized seizures. Using a homozygous diabetic mouse model (ob/ob), treatment with topiramate resulted to a significantly lower levels of blood glucose, triglycerides, and insulin and glycosylated hemoglobin than in control ob/ob mice not given topiramate. According to the inventors, these findings demonstrate that topiramate can reduce or prevent pathophysiological signs associated with syndrome X. In addition, the amelioration of diabetic condition by topiramate is not dependent on a reduction in body weight.
Although drug therapy has proven to be effective in reducing and treating insulin resistance, adult onset diabetes, and MS-X and its related complications, it leads to side effects, such as weight gain, water retention, slight risk of cardiac events and hypoglycemia, gastrointestinal problems including nausea, flatulence, and diarrhea, lactic acidosis, reduced absorption of vitamin B12 and folic acid, and reduced iron absorption.
Accordingly, there is a need to provide an improved method of treating the above-mentioned conditions that avoids or minimizes these side effects. There is a continuing need to provide an early method for treating these conditions to avoid the emergence of costly and disabling degenerative conditions, as described above.